Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharides (LPS) are proinflammatory bacterial products implicated in the pathogenesis of gram-negative sepsis and septic shock. Polymyxin B (PMB), a cyclic, cationic peptide antibiotic, inhibits biological activities of LPS through high-affinity binding to the lipid A moiety. Small synthetic peptides have been designed to mimic the primary and secondary structures of PMB to determine structural requirements for binding and detoxification of lipid A and to assess possible therapeutic potential. The purpose of this study was to compare and contrast the endotoxin-neutralizing activities of two synthetic antiendotoxin peptides (SAEP-2 and SAEP-4), PMB, and an LPS core-specific monoclonal antibody (MAb), WN1 222-5, based on their abilities to inhibit CD14-mediated target cell uptake of fluorescein isothiocyanate (FITC)-conjugated LPS, detected by flow cytometry and confocal microscopy, and LPS-induced production of the proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), as measured by bioassays. PMB and SAEP-4 produced dose-dependent inhibition of FITC-LPS uptake by CD14-transfected Chinese hamster ovary fibroblasts (CHO-CD14 cells) and by human peripheral blood mononuclear cells. The anti-LPS MAb, WN1 222-5, also blocked LPS uptake by these cells and synergized with PMB and SAEP-4. LPS-induced IL-6 release was inhibited by PMB, SAEP-4, and MAb WN1 222-5, and these inhibitory activities were additive or synergistic. LPS-induced TNF-alpha release by PBMC was also inhibited by PMB and SAEP-4 alone and in combination with anti-LPS MAb. SAEP-2, in contrast, produced comparatively minor decrements in cellular uptake of LPS and LPS-induced cytokine responses, and did so only in the absence of serum, while a nonsense peptide exerted no discernible inhibitory effect on LPS uptake or LPS-induced cytokine expression in the presence or absence of serum. Thus, PMB and SAEP-4, like the LPS-reactive MAb, WN1 222-5, block proinflammatory activities of LPS in part by preventing LPS recognition by membrane-bound CD14-expressing target cells. Differences in peptide structure, however, like those exemplified by SAEP-2 and SAEP-4, may differentially affect the endotoxin-neutralizing potency of these peptides despite similar binding activity against lipid A, reflecting possible differences in peptide solubility or peptide regulation of intracellular signal transduction.
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PMID:Influence of synthetic antiendotoxin peptides on lipopolysaccharide (LPS) recognition and LPS-induced proinflammatory cytokine responses by cells expressing membrane-bound CD14. 1067 85

Cytokines and other paracrine or autocrine factors functionally modulate the invasion-suppressor and signal-transducing E-cadherin/catenin complex. We have used conditioned medium from human squamous carcinoma COLO 16 cells (CM COLO 16) as a source of such factors to modulate the E-cadherin/catenin complex in human breast carcinoma MCF-7 cells. CM COLO 16 induces scattering of MCF-7/AZ, but not of MCF-7/6 cells on tissue culture plastic substratum, and reduces aggregation of MCF-7/AZ cells in suspension. Insulin-like growth factor I counteracts this reduction of aggregation. Confocal laser scanning microscopy of immunocytochemical stainings shows loss of the honeycomb pattern of E-cadherin, alpha-catenin and beta-catenin, and internalization of those elements. Cell surface biotinylation shows a decrease in membrane-bound E-cadherin. Immunoprecipitation and cell fractionation show that the composition of the complex is maintained. Interleukin-1, interleukin-6, granulocyte-monocyte colony stimulating factor, stem cell factor, scatter factor/hepatocyte growth factor and transforming growth factor-beta, added separately to MCF-7/AZ cells, could not mimic the effects of CM COLO 16. Neither could we find evidence that the 80 kDa extracellular fragment of E-cadherin is implicated in scattering of MCF-7/AZ cells. This fragment is present in CM COLO 16, but it is also produced by the MCF-7/AZ cells themselves, even at higher levels. Our data point toward cytoplasmic internalization induced by paracrine factors as one of the downregulating mechanisms for the E-cadherin/catenin complex.
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PMID:Internalization of the E-cadherin/catenin complex and scattering of human mammary carcinoma cells MCF-7/AZ after treatment with conditioned medium from human skin squamous carcinoma cells COLO 16. 1071 91

The receptor for interleukin-6 (IL-6) consists of two subunits: a ligand specific IL-6Ralpha and gp130 that is responsible for signal-transduction. A soluble form of the ligand specific chain was described that when complexed to IL-6 is capable of binding to the membrane-bound gp130 subunit and thus can elicit signal-transduction. This soluble receptor can act on cells that express only the gp130 but not the ligand-specific subunit of the IL-6R. This phenomenon, called trans-signaling, introduced a novel aspect of cytokine action. In this study we examined the response of Jurkat cells, that are known not to express IL-6Ralpha, to IL-6, the soluble IL-6 receptor (sIL-6R) and a covalent complex of IL-6 and sIL-6R termed Hyper-IL-6. We studied the expression of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma). The complex of IL-6+sIL-6R and Hyper-IL-6 inhibited significantly the production of TNF in a gp130-dependent manner, whereas no differences in IFN-gamma expression were found. IL-6 and sIL-6R alone were not effective. Because we did not detect major differences in the TNF mRNA levels upon treatments, we conclude that the inhibition of TNF production should occur at the post-transcriptional level. These results provide another example of trans-signaling and underline the physiological importance of sIL-6R, and in the case of Hyper-IL-6 its possible therapeutic application can also be considered.
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PMID:Soluble interleukin-6 receptor (sIL-6R) makes IL-6R negative T cell line respond to IL-6; it inhibits TNF production. 1072 65

The cytokine interleukin-6 (IL-6) has multiple functions in the immune and hematopoietic systems. IL-6 is related to ciliary neurotrophic factor (CNTF), a trophic factor for motoneurons, sensory dorsal root ganglion (DRG) neurons, and other neuronal subpopulations. Both act via related receptor complexes, consisting of one ligand-specific alpha-receptor subunit (IL-6R and CNTFR, respectively) and two signal-transducing receptor components. Even though IL-6 is expressed by neurons and glia, the functions of IL-6 in the nervous system are poorly understood. Here, we report that exogenous human IL-6 promotes the survival of dissociated newborn rat DRG neurons in vitro if supplemented with soluble human IL-6-alpha-receptor. The dosages of human IL-6 and soluble human IL-6R necessary to achieve neurotrophic effects could be reduced markedly by linking ligand and alpha-receptor component in a designer cytokine. Furthermore, we show that newborn rat DRG neurons express and secrete bioactive IL-6. Endogenously secreted IL-6 does not enhance survival of these neurons in vitro, suggesting that DRG neurons do not sufficiently express cell surface IL-6R. Exogenously added soluble rat IL-6R rendered DRG neurons responsive to secreted IL-6. Our results indicate an autocrine function of IL-6 in DRG neuron survival which depends on membrane-bound or soluble IL-6R as a neurotrophic cofactor.
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PMID:Interleukin-6 (IL-6) and its soluble receptor support survival of sensory neurons. 1072 52

Interleukin-6 (IL-6), a major cytokine with diverse effects on cells mainly of the immune and hematopoietic systems, has been linked to several neurological disorders such as acquired immune deficiency syndrome dementia, multiple sclerosis, and Alzheimer's disease. Central nervous system (CNS)-specific expression of IL-6 caused neurodegeneration, massive gliosis, and vascular proliferation in transgenic mice. However, the effects of systemically circulating IL-6 and its receptor IL-6Ralpha on the CNS are unknown. IL-6Ralpha is the specific component of the IL-6 receptor system and hence an important co-factor of IL-6. IL-6Ralpha is bioactive in a membrane-bound and in a soluble (s) form. We investigated the effects of systemically elevated levels of either human IL-6 or human sIL-6Ralpha or both on the CNS of transgenic mice. Although IL-6 and sIL-6Ralpha single transgenic mice were free of neurological disease, IL-6/sIL-6Ralpha double-transgenic mice showed neurological signs, such as tremor, gait abnormalities, and paresis. However, these mice also frequently showed prominent general weakness probably because of the systemic effects of IL-6/IL-6Ralpha such as liver damage and plasmacytomas. IL-6/sIL-6Ralpha transgenic mice exhibited massive reactive gliosis. Lack of signs of neuronal breakdown versus ample astrogliosis suggested that astrocytes were selectively affected in these mice. There was neither vascular proliferation nor inflammatory infiltration. Ultrastructural analysis revealed blood-brain barrier (BBB) changes manifested by hydropic astrocytic end-feet. However, albumin immunohistochemistry did not reveal major BBB leakage. Our results indicate that increased and constitutive systemic expression of IL-6 together with its soluble receptor sIL-6Ralpha is less harmful to the brain than to other organs. The BBB remains primarily intact. IL-6/IL-6Ralpha, however, might be directly responsible for the selective activation of astrocytes.
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PMID:Astrocytic alterations in interleukin-6/Soluble interleukin-6 receptor alpha double-transgenic mice. 1107 9

Human osteoblasts produce interleukin-6 (IL-6) and respond to IL-6 in the presence of soluble IL-6 receptor (sIL-6R), but the cell surface expression of IL-6R and the mechanism of sIL-6R production are largely unknown. Three different human osteoblast-like cell lines (MG-63, HOS, and SaOS-2) and bone marrow-derived primary human osteoblasts expressed both IL-6R and gp130 as determined by flow cytometry and immunoprecipitation. However, the membrane-bound IL-6R was nonfunctional, as significant tyrosine phosphorylation of gp130 did not occur in the presence of IL-6. Phorbol myristate acetate induced a dramatic increase of both IL-6R shedding (i.e. the production of sIL-6R) and IL-6 release in osteoblast cultures, but the cell surface expression of gp130 remained unchanged. IL-6 complexed with sIL-6R, either exogenously introduced or derived from the nonfunctional cell surface form by shedding, induced rapid tyrosine phosphorylation of gp130. This effect was inhibited by neutralizing antibodies to either sIL-6R or gp130, indicating that the gp130 activation was induced by IL-6/sIL-6R/gp130 interaction. Protein kinase C inhibitors blocked phorbol myristate acetate-induced and spontaneous shedding of IL-6R resulting in the absence of sIL-6R in the culture medium, which in turn also prevented the activation of gp130. In conclusion, human osteoblasts express cell surface IL-6R, which is unable to transmit IL-6-induced signals until it is shed into its soluble form. This unique mechanism provides the flexibility for osteoblasts to control their own responsiveness to IL-6 via the activation of an IL-6R sheddase, resulting in an immediate production of functionally active osteoblast-derived sIL-6R.
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PMID:Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. 1188 3

Interleukin-6 (IL-6) contributes to increased pain and hyperalgesia in inflamed tissue. We have investigated the effects of IL-6, alone or in combination with its soluble receptor (sIL-6R), on the sensitivity of nociceptors to noxious heat, using dermal microdialysis. Plasmapheresis membranes were inserted into the abdominal skin of adult male Wistar rats (n=46) and perfused with modified Ringer solution. After three control samples (20 min each), the skin area above the membrane was heated to 48 degrees C for 20 min. The stimulation was followed by two washout samples. The calcitonin gene-related peptide (CGRP) content of the dialysate was measured with an enzyme immunoassay. Heat stimulation provoked a significant CGRP increase in the dialysate. Intradermal application of IL-6 (200 ng ml-1) did not significantly alter heat-induced CGRP release. However, a significant sensitisation of the heat-induced CGRP release was observed when sIL-6R (25 ng ml-1) was applied, either alone or in combination with IL-6. Neutralisation of endogenous IL-6 with a sheep anti-rat IL-6 serum did not alter heat-induced CGRP release, but abolished the sIL-6R-mediated sensitising effect. We show that IL-6 in combination with its soluble receptor can sensitise nociceptors to heat and provide evidence for the constitutive expression of the signalling molecule gp130, but not of the IL-6-membrane-bound (specific) receptor, in nociceptors.
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PMID:Interleukin-6 in combination with its soluble IL-6 receptor sensitises rat skin nociceptors to heat, in vivo. 1193 61

The pathological role of interferon-gamma (IFN-gamma) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ATP-binding cassette transporter 1(ABC1) message and protein levels were decreased 3- to 4-fold in foam cells by IFN-gamma. In the present study, the pathway by which IFN-gamma inhibited ABC1 expression was investigated with signal transducers and activators of transcription (Stat1) knockout mice. IFN-gamma-stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN-gamma treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN-gamma was intact in the Stat1 KO macrophages, inasmuch as IFN-gamma was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN-gamma on cholesterol efflux and ABC1 expression.
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PMID:Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway. 1200 10

Interleukin-6 (IL-6) binds to a receptor complex consisting of an 80 kDa binding unit (IL-6R) and gp130 responsible for signal transduction. Due to alternative splicing and/or proteolytic digestion IL-6R occurs in soluble form (sIL-6R), as well. Soluble IL-6R is able to bind to gp130 expressing on nucleated cells, thus sIL-6R makes most cells responsive to IL-6. In this study we found that oncostatin M (OSM), an other gp130 dependent cytokine with proliferation inhibitory potential, increases the expression of both membrane-bound IL-6R and sIL-6R generated by alternative splicing in hepatic and mammary carcinoma cell lines. Furthermore, we studied the functional relevance of the presence and binding of soluble IL-6R to HepG2 cells. Using a cDNA expression array, mRNA levels of about 580 human genes were tested by differential display analysis. Our findings suggest, that elevation of surface density of IL-6R by attachment of sIL-6R induces major modulation in gene expression profile of the hepatoma cells. Soluble IL-6R alone has minor effect, it rather decreases expression of some genes, while incubation with IL-6 and sIL-6R together induces major changes in the mRNA pattern of HepG2 cells. These data strongly suggest that presence and binding of soluble cytokine receptors are important elements of inter-cytokine cross talk and affects actual gene expression profile of responding cells.
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PMID:Soluble interleukin-6 receptor enhanced by oncostatin M induces major changes in gene expression profile of human hepatoma cells. 1200 38

Tolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.
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PMID:Induction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression. 1213 36


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